Project Summary/Abstract The goal of this proposal is to develop a novel high-throughput platform for understanding gene regulatory elements in order to identify new drug targets for common diseases. The human genome encodes approximately 50,000 genes. Understanding how those genes are regulated and how this correlates to complex cell phenotypes has long been a major focus of our team. Follow-up projects to the Human Genome Project, such as the NIH-funded Encyclopedia of DNA Elements (ENCODE) and the Roadmap Epigenomics Project, have identified millions of putative regulatory elements across the human genome for many human cell types and tissues. Importantly, genome wide association (GWA) studies have strongly indicated that non- coding regulatory elements determine the gene expression patterns responsible for most complex diseases including cancer, cardiovascular disease, diabetes, and neurological disorders. However, the function of these regulatory elements and their relationships to these disease phenotype are largely unknown. Additionally, conventional screening technologies for perturbing cellular processes, such as small molecules and RNA interference, cannot directly target genomic regulatory elements. To address this critical limitation and illuminate the fundamental genomic basis of these cell phenotypes, we have recently developed epigenome- editing technologies for directly and precisely activating and repressing genomic regulatory elements in their natural chromosomal location. More recently, we have developed a novel and robust method for using these tools for high-throughput identification and quantification of gene regulatory element activity. Here, we propose to apply these methods to the discovery and validation of regulatory elements associated with cancer and cardiovascular disease as demonstration of this novel platform technology for understanding the genetic basis of complex disease. This technology will be critical to translating modern advances in genetics and genomics into new drug targets, diagnostics, and personalized medicine catered to each patient genome.